Mapping the energetic and allosteric landscapes of protein binding domains.

Autor: Faure AJ; Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain., Domingo J; Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.; New York Genome Center (NYGC), New York, NY, USA., Schmiedel JM; Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain., Hidalgo-Carcedo C; Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain., Diss G; Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.; Friedrich Miescher Institute for Biomedical Research (FMI), Basel, Switzerland., Lehner B; Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain. ben.lehner@crg.eu.; Universitat Pompeu Fabra (UPF), Barcelona, Spain. ben.lehner@crg.eu.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. ben.lehner@crg.eu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Apr; Vol. 604 (7904), pp. 175-183. Date of Electronic Publication: 2022 Apr 06.
DOI: 10.1038/s41586-022-04586-4
Abstrakt: Allosteric communication between distant sites in proteins is central to biological regulation but still poorly characterized, limiting understanding, engineering and drug development 1-6 . An important reason for this is the lack of methods to comprehensively quantify allostery in diverse proteins. Here we address this shortcoming and present a method that uses deep mutational scanning to globally map allostery. The approach uses an efficient experimental design to infer en masse the causal biophysical effects of mutations by quantifying multiple molecular phenotypes-here we examine binding and protein abundance-in multiple genetic backgrounds and fitting thermodynamic models using neural networks. We apply the approach to two of the most common protein interaction domains found in humans, an SH3 domain and a PDZ domain, to produce comprehensive atlases of allosteric communication. Allosteric mutations are abundant, with a large mutational target space of network-altering 'edgetic' variants. Mutations are more likely to be allosteric closer to binding interfaces, at glycine residues and at specific residues connecting to an opposite surface within the PDZ domain. This general approach of quantifying mutational effects for multiple molecular phenotypes and in multiple genetic backgrounds should enable the energetic and allosteric landscapes of many proteins to be rapidly and comprehensively mapped.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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